This application relates to heterologous stimulus-gated ion channels, and to the triggering of such channels, when expressed in cells, to selectively activate those cells.
The activation of a cell is defined as a shift in the electrical potential across the plasma membrane of the cell from a resting (or polarized) value to an excited (or depolarized) value, or as an increase in the intracellular concentration of calcium ion from a resting (or basal) value to an elevated value. Cellular activation via membrane potential shifts underlies, for example, neuronal activity; sensory transduction; the contraction of skeletal, cardiac, and smooth muscle; and glucose sensing by beta-cells of the pancreas. Cellular activation via increases in the concentration of calcium ion underlies, for example, exocrine, endocrine, and paracrine secretion; chemical neurotransmission; the contraction of skeletal, cardiac, and smooth muscle; cell death; and T-cell activation. Being able to regulate any or all of these processes selectively has important implications for biological research, drug discovery, and medicine.
Mechanistically, the activation of a cell is effected by transmembrane ion channels whose conducting pores open and close (are “gated”) in response to physical or chemical stimuli. Known physical stimuli that gate ion channels include changes in membrane potential (voltage-gated channels), mechanical stress (mechanosensitive channels), or temperature (temperature-sensitive channels). Known chemical stimuli that gate ion channels include changes in the concentrations of intracellular messengers (e.g., calcium- and cyclic-nucleotide-gated channels) or extracellular signaling molecules (e.g., ionotropic neurotransmitter receptors).